Germline BRCA-Mutated HER2-Negative Advanced Breast Cancer: Overcoming Challenges in Genetic Testing and Clinical Considerations When Using Talazoparib.

Genetic testing is essential to the diagnosis and management of patients with breast cancer. For example, women who carry mutations in BRCA1/2 genes have an increased lifetime risk of breast cancer and the presence of these mutations may sensitize the patient to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. Two PARP inhibitors are approved by the US Food and Drug Administration for patients with germline BRCA-mutated advanced breast cancer (olaparib and talazoparib). The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer (Version 2.2023) recommend that all patients with recurrent or metastatic breast cancer (mBC) be assessed for the presence of germline BRCA1/2 mutations. However, many women eligible for genetic testing do not receive it. Here, we provide our perspectives on both the importance of genetic testing and the challenges patients and community clinicians may face when trying to access genetic testing. We also present a hypothetical case study involving a female patient with germline BRCA-mutated human epidermal growth factor receptor 2 (HER2)-negative mBC to highlight potential clinical considerations on the use of talazoparib, including the decision to initiate therapy, dosing considerations, potential drug-drug interactions, and managing side effects. This case illustrates the benefits of a multidisciplinary approach to managing patients with mBC and involving the patient in the decision-making process. This patient case is fictional and does not represent events or a response from an actual patient; this fictional case is for educational purposes only.

Experimental and theoretical bases of specific affinity, a cytoarchitecture-based formulation of nutrient collection proposed to supercede the Michaelis-Menten paradigm of microbial kinetics.

A theory for solute uptake by whole cells was derived with a focus on the ability of oligobacteria to sequester nutrients. It provided a general relationship that was used to obtain the kinetic constants for in situ marine populations in the presence of naturally occurring substrates. In situ affinities of 0.9 to 400 liters g of cells(-1) h(-1) found were up to 10(3) times smaller than those from a "Marinobacter arcticus " isolate, but springtime values were greatly increased by warming. Affinities of the isolate for usual polar substrates but not for hydrocarbons were diminished by ionophores. A kinetic curve or Monod plot was constructed from the best available data for cytoarchitectural components of the isolate by using the theory together with concepts and calculations from first principles. The order of effect of these components on specific affinity was membrane potential > cytoplasmic enzyme concentration > cytoplasmic enzyme affinity > permease concentration > area of the permease site > translation coefficient > porin concentration. Component balance was influential as well; a small increase in cytoplasmic enzyme concentration gave a large increase in the effect of permease concentration. The effect of permease concentration on specific affinity was large, while the effect on K(m) was small. These results are in contrast to the Michaelis-Menten theory as applied by Monod that has uptake kinetics dependent on the quality of the permease molecules, with K(m) as an independent measure of affinity. Calculations demonstrated that most oligobacteria in the environment must use multiple substrates simultaneously to attain sufficient energy and material for growth, a requirement consistent with communities largely comprising few species.